SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

Trends in Microbiology, Journal Year: 2015, Volume and Issue: 23(11), P. 680 - 692

Published: Oct. 3, 2015

Language: Английский

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Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of Thr-592

Journal of Biological Chemistry, Journal Year: 2015, Volume and Issue: 290(44), P. 26352 - 26359

Published: Aug. 21, 2015

Language: Английский

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SAMHD1 specifically restricts retroviruses through its RNase activity

Retrovirology, Journal Year: 2015, Volume and Issue: 12(1)

Published: June 2, 2015

Human SAMHD1 possesses dual enzymatic functions. It acts as both a dGTP-dependent triphosphohydrolase and an exoribonuclease. The dNTPase function depletes the cellular dNTP pool, which is required for retroviral reverse transcription in differentiated myeloid cells resting CD4(+) T cells; thus this activity mainly plays role SAMHD1-mediated restriction. However, recent study demonstrated that directly targets HIV-1 genomic RNA via its RNase activity, (rather than activity) sufficient While potent target during viral infection, specificity of infection by other viruses unclear.The results present showed specifically degrades monocyte-derived macrophage-like primary macrophages. Consistent with this, selectively restricted replication, but did not affect replication common non-retro genome viruses, suggesting RNase-mediated antiviral limited to retroviruses. In addition, neither inhibiting treatment several transcriptase inhibitors nor transcriptase-defective altered levels after challenge, indicating retrovirus-specific dependent on processes associated transcription.The presented herein suggest control retroviruses, viruses.

Language: Английский

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Conserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication

Cell Reports, Journal Year: 2019, Volume and Issue: 28(2), P. 449 - 459.e5

Published: July 1, 2019

Highlights•SAMHD1 depletion facilitates EBV lytic replication•EBV protein kinase BGLF4 directly phosphorylates SAMHD1•BGLF4 phosphorylation of SAMHD1 inhibits its dCTPase and dTTPase activity•SAMHD1 is targeted by the conserved herpesvirus kinasesSummaryTo ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance host anti-viral responses. Sterile alpha motif HD domain 1 (SAMHD1) was recently identified as an intrinsic restriction factor for variety viruses. Aside from HIV-2 related simian immunodeficiency virus (SIV) Vpx proteins, direct viral countermeasures against remain unknown. Using Epstein-Barr (EBV) primary model, we discover that SAMHD1-mediated antagonized BGLF4, member kinases encoded all herpesviruses. Mechanistically, find thereby deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity. We further demonstrate targeting common feature shared beta- gamma-herpesviruses. Together, our findings uncover immune evasion mechanism whereby exploit thwart defenses.Graphical abstract

Language: Английский

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SAMHD1 protects cancer cells from various nucleoside-based antimetabolites

Cell Cycle, Journal Year: 2017, Volume and Issue: 16(11), P. 1029 - 1038

Published: April 24, 2017

Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), most important drug AML treatment. Ara-C intracellularly converted by canonical dNTP synthesis pathway ara-CTP, which serves as substrate but not an allosteric activator SAMHD1. Using mouse model, show here wild type catalytically inactive SAMHD1 reduces ara-C treatment efficacy vivo. Expanding clinically relevant substrates SAMHD1, demonstrate THP-1 CRISPR/Cas9 lacking functional gene showed increased sensitivity antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, trifluridine. Within this Extra View, discuss build upon both these our previously reported findings, propose likely active against variety nucleoside analog present anti-cancer chemotherapies. Thus, may constitute promising target improve wide range therapies for hematological non-haematological malignancies.

Language: Английский

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SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation

Cell Reports, Journal Year: 2019, Volume and Issue: 28(2), P. 434 - 448.e6

Published: July 1, 2019

Highlights•HCMV infection induces SAMHD1 expression and phosphorylation•SAMHD1 restricts HCMV gene before virus replication•SAMHD1 deficiency limits entry into the quiescent stage of infection•HCMV restriction by is mediated limiting NF-κB activationSummaryCellular inhibits replication many viruses intracellular deoxynucleoside triphosphate (dNTP) pools. We investigate influence on human cytomegalovirus (HCMV). During infection, we observe induction, accompanied phosphorylation via viral kinase UL97. depletion increases in permissive fibroblasts conditionally myeloid cells. show this due to enhanced from major immediate-early (MIE) promoter independent dNTP levels. suppresses innate immune responses inhibiting nuclear factor κB (NF-κB) activation. that regulates MIE through Chromatin immunoprecipitation reveals increased RELA RNA polymerase II absence SAMHD1. Our studies reveal a mechanism how activates an pathway paradoxically results transcriptional activation promoter.Graphical abstract

Language: Английский

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Structural Basis of Allosteric Activation of Sterile α Motif and Histidine-Aspartate Domain-containing Protein 1 (SAMHD1) by Nucleoside Triphosphates

Journal of Biological Chemistry, Journal Year: 2014, Volume and Issue: 289(47), P. 32617 - 32627

Published: Oct. 7, 2014

Language: Английский

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SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

Biochemical and Biophysical Research Communications, Journal Year: 2014, Volume and Issue: 455(3-4), P. 229 - 233

Published: Nov. 6, 2014

Language: Английский

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Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle

Scientific Reports, Journal Year: 2016, Volume and Issue: 6(1)

Published: May 27, 2016

Abstract Deoxynucleotide triphosphates (dNTPs) are essential for efficient hepatitis B virus (HBV) replication. Here, we investigated the influence of restriction factor SAMHD1, a dNTP hydrolase (dNTPase) and RNase, on HBV We demonstrated that silencing SAMHD1 in hepatic cells increased replication, while overexpression had opposite effect. significantly affected levels extracellular viral DNA as well intracellular reverse transcription products, without affecting RNAs or cccDNA. mutations interfere with dNTPase activity (D137N) catalytic center histidine-aspartate (HD) domain (D311A), phospho-mimetic mutation (T592E), abrogated inhibitory activity. In contrast, diminishing potential RNase but not (Q548A) disabling phosphorylation (T592A) did affect antiviral Moreover, by was rescued addition deoxynucleosides. Although infection directly protein level upregulated dATPs. Interestingly, dephosphorylated, thus potentially antiviral-active state, primary human hepatocytes. Furthermore, type I II interferons cells. These results suggest is relevant restricts through its

Language: Английский

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Low dNTP levels are necessary but may not be sufficient for lentiviral restriction by SAMHD1

Virology, Journal Year: 2015, Volume and Issue: 488, P. 271 - 277

Published: Dec. 4, 2015

Language: Английский

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